Method of administration of a pulmonary surfactant

ABSTRACT

The present invention concerns a method for treating a respiratory distress in a infant in need of such treatment, the method comprising intratracheal administration of a pulmonary surfactant by a thin tube. 
     The invention also concerns a kit for performing said method.

FIELD OF INVENTION

The present invention concerns a method for preventing and/or treatingrespiratory distress syndrome in infants in need of such treatment, themethod comprising intratracheal administration of a pulmonary surfactantby a thin tube. The invention also concerns a kit for performing saidmethod.

BACKGROUND OF THE INVENTION

The human lung is composed of a large number of small air sacs, calledalveoli, in which gases are exchanged between the blood and the airspaces of the lungs. In healthy individuals, this exchange is mediatedby the presence of a protein-containing surfactant complex that preventsthe lungs from collapsing at the end of expiration.

Lung surfactant complex is composed primarily of lipids and containsminor amounts of various proteins. An absence of adequate levels of thiscomplex results in malfunction of the lung. This syndrome is calledRespiratory Distress Syndrome (RDS) and is the single most importantcause of morbidity and mortality in pre-term infants.

RDS is mainly treated with replacement therapy whereby exogenouspulmonary surfactant preparations extracted from animal lungs, known asmodified natural surfactants are administered to the human in need. Forinstance, modified natural surfactants used in the clinical practice areporactant alfa derived from porcine lung, and sold under the trademarkof Curosurf®, beractant (Surfacten® or Survanta®) bovactant(Alveofact®), both derived from bovine lung, and calfactant derived formcalf lung (Infasurf®).

Synthetic surfactants mimicking the composition of the modified naturalsurfactants, and known as reconstituted surfactants, have also beendeveloped.

Exogenous pulmonary surfactants are currently administered byendotracheal instillation as suspension in a saline aqueous solution tointubated pre-term infants kept under intermittent positive pressureventilation (IPPV). However, IPPV is in itself an invasive procedurewhich frequently requires supplemental medication like treatment withsedatives, analgesic agents and catecholamines.

Furthermore IPPV in pre-term infants with RDS has long been recognizedto contribute to lung injury which may lead to the development ofpneumothorax and/or bronchopulmonary dysplasia (BDP); and may causereduction of mucociliary clearance, mucosal injury, and secondaryinfections as well as blockage of the endotracheal.

In view of the potential complications associated with intubation andmechanical ventilation, attention has been focused on differentapproaches of administration of exogenous surfactant.

Since long time, as a possible initial respiratory support for very lowbirth weight (VLBW) infants, use of early nasal Continuous PositiveAirway Pressure (nCPAP), that delivers air into the lungs throughspecially designed nasal devices such as masks, prongs or tubes, hasbeen introduced in neonatal intensive care.

Recently, to give exogenous surfactant without mechanical ventilation,the use of a thin gastric tube placed in the trachea supported withnCPAP has been proposed (Gopel W et al, abstract presented at the 20thInternational Workshop on Surfactant Replacement, Belfast, Jun. 2-5,2005, page 12: Kribs, A et al. Paediatr Anaesth. 2007 Apr;17(4):364-9.).

In particular, Gopel W and colleagues reported on the administration of60 mg bovine surfactant, diluted to 30 mg/ml, by a 5 Fr gastric tube inspontaneously breathing infants with a mean weight of about 1 kg.

However, to improve the clinical outcome, an initial dose higher than 60mg/kg body weight, is currently recommended. A dose higher than 60 mg/kgrequires a higher concentration of the surfactant preparation to beused, in particular of at least 40 mg/ml.

Since viscosity increases with surfactant concentration, theadministration of a concentration of at least 40 mg/ml, by means of agastric tube that has a very small diameter (5 Fr. corresponds to about1.7 mm) would be only possible with a surfactant having low viscosity.In fact high viscosities would make the passage of the surfactantthrough the gastric tube and the small airways more difficult and maytherefore result in uneven distribution in the lungs of the pre-terminfants. Theoretically, surfactants having high viscosities carry therisk of blockage of the gastric tube and of acute airway obstruction.

In view of the drawbacks of the methods previously used for delivery ofexogenous surfactant, alternative therapeutic methods for surfactantadministration are needed. Such methods should provide at leastidentical or, preferably improved clinical outcome without the potentialcomplications associated to endotracheal intubation and mechanicalventilation.

The therapeutic methods and kits disclosed herein provide a realimprovement over therapies described in the art.

SUMMARY OF THE INVENTION

The present invention contemplates a method for preventing and/ortreating a respiratory distress syndrome in a patient in need of suchtreatment, said method comprising the steps of:

-   -   a) applying nasal Continuous Positive Airway Pressure (nCPAP)        with a nasal device to said infant at a pressure of from 1 to 12        cm water;    -   b) administering a pulmonary surfactant suspended in a        pharmaceutically acceptable aqueous medium via a tube having a        diameter comprised between 5 and 12 Fr, preferably a gastric        tube, into the trachea of said infant; and    -   c) removing said tube at the end of the administration; wherein        the surfactant suspension is applied at a concentration of at        least 40 mg/ml and has a viscosity lower than 20 mPas.

The invention is also directed to a kit comprising: a) a sterilepharmaceutical composition comprising a pulmonary surfactant having aviscosity lower than 20 cpoise suspended in a pharmaceuticallyacceptable aqueous medium at a concentration of at least 40 mg/ml; b) athin tube having a diameter comprised between 5 and 12 Fr; c) a devicefor administering the surfactant at a controlled rate; and d) containermeans for containing the dosage form, the thin tube and the device.

DEFINITIONS

The term “modified natural surfactant” means a lipid extract of mincedmammalian lung which, due to the lipid extraction step used in themanufacture process, is deprived of the hydrophilic proteins SP-A andSP-D and contains variable amounts of the hydrophobic proteins SP-B andSP-C. Depending on the method of extraction, the preparation may containnon-surfactant lipids and other components.

The term “reconstituted surfactant” means a synthetic surfactant made ofa mixture of polar lipids, primarily phospholipids and optionally othercomponents such as neutral lipids to which have been added surfactantproteins/peptides isolated from animals or proteins/peptidesmanufactured through recombinant technology such as those described inWO 95/32992, or synthetic surfactant protein analogues such as thosedescribed in WO 89/06657, WO 92/22315 and WO 00/47623.

“Pharmaceutical acceptable” is a term used herein that refers to amedium that does not produce an allergic or similar untoward reactionwhen administered to an infant.

The expression “improving the clinical outcome” means a surfactant withan improved efficacy in terms of indices of activity, i.e lungcompliance, lung gas volume, blood gases and ventilator settings.

DETAILED DISCLOSURE OF THE INVENTION

The present invention discloses a method of preventing and/or treating arespiratory distress syndrome, said method comprises the steps of:

a) applying nasal Continuous Positive Airway Pressure (nCPAP) with anasal device to said infant at a pressure of about 1 to 12 cm water;

b) administering a pulmonary surfactant suspended in a pharmaceuticallyacceptable aqueous medium via a tube having a diameter comprised between5 and 12 Fr into the trachea of said infant; and

c) removing said tube at the end of the administration; wherein thesurfactant suspension is applied at a concentration of at least 40 mg/mland has a viscosity lower than 20 mPas.

Advantageously, the method of the invention is applied to pre-termvery-low-birth-weight-infants infants of 24-35 weeks gestational agethat are spontaneously breathing, and demonstrate early signs ofrespiratory distress syndrome as indicated either by clinical signsand/or supplemental oxygen demand (fraction of inspired oxygen(FiO₂)>30%). The treatment shall start preferably in the first 24 h oflife.

The method of the invention is directed to the prevention and/ortreatment of the respiratory distress syndrome on the infant related toa surfactant-deficiency or dysfunction (RDS) as well as of conditions inwhich respiratory distress may be present that include, but are notlimited to, meconium aspiration and pulmonary infection.

The method of the invention may also be useful for preventing and/ortreating acute respiratory distress syndrome in children or adults.

The method of the invention comprises applying nasal Continuous PositiveAirway Pressure (nCPAP) with a nasal device such as a mask, prongs, or apharyngeal tube according to procedures well known to the person skilledin the art.

Preferably a nasal mask is utilised. Any nasal mask commerciallyavailable may be used, for example those provided by The CPAP Store LLC,and the CPAP Company.

Nasal CPAP is typically applied at a pressure comprised between 1 and 12cm water, preferably 2 and 8 cm water, although the pressure can varydepending on the infant and the pulmonary condition.

The application of nCPAP is advantageously carried out to the infantprior to administering the surfactant and continuously throughout theprocedure during both the administering and the removing steps.

Optionally, prior to the procedure, atropine is administered i.v. at 5μg/kg body weight. Sedative and/or analgesic drugs can optionally beadministered as well.

Before administering the pulmonary surfactant, the gastric tube isplaced with a Magill-forceps under direct visualization of the vocalcords of the infants by means of a laryngoscope. After placement of thegastric tube, the laryngoscope is removed and the pulmonary surfactantis administered by instillation in the trachea at controlled rate with asuitable device.

The pulmonary surfactant in the form of suspension is administered bymeans of a tube having a diameter comprised between 5 and 12 Fr. Anygastric or nasogastric tube, arterial or suction catheter of common usein the hospital can be utilised for the purpose of the invention.

The tube may be made of any material, preferably of polyurethane orsilicone.

Preferably a 5 Fr tube is used because it has a small diameter, but atthe same time it is stiff enough to allow easy introduction with theMagill forceps. Preferably a cm-scale is marked on the tube to allow thecorrect length of introduction.

If the tube has side holes, such holes should not be too far away fromthe catheter tip. The connector to the syringe should be small too avoidunnecessary dead space.

Preferably the tube has a total length of about 30 cm to allow a lengthof about 10 cm in the oral cavity/nasopharynx and a length of about 20cm outside for easy handling.

Suitable devices include syringes having a small dead volume, preferablyof less than 0.5 ml, more preferably of less than 0.3 ml or, infusionpumps.

Depending of the volume to be administered, the person skilled in theart shall control the rate of delivering of the device so as to instilthe surfactant in a time ranging from 1 to 5 minutes, preferably from 1to 3 minutes.

The pulmonary surfactant is administered as a suspension in a sterilepharmaceutically acceptable aqueous medium, preferably in a bufferedphysiological saline aqueous solution, more preferably buffered at a pHfrom 5.5 to 6.5.

The concentration of the surfactant is of at least 40 mg/ml, preferablyfrom 40 to 80 mg/ml.

The applied volume should be not more than 3.0 ml, preferably not morethan 2 ml and depending on the concentration of the surfactant and deadvolume of the syringe.

Any modified natural- or reconstituted surfactant can be used providedthat the relevant suspension in an aqueous medium has a viscosity lowerthan 20 mPas (1 mPas coresponds to 1 centipoise), preferably comprisedbetween 5 and 15 mPas, more preferably comprised between 6 and 10 mPas.

The viscosity may be determined by any known method. Preferably, theviscosity is determined according to the method reported in Example 1.

In particular, it has been found that, due to its low viscosity, themodified natural surfactant poractant alfa is particularly suitable forbeing administered by a gastric tube. In particular its low viscosityallows administering the surfactant at a concentration of at least 40mg/ml.

Advantageously, the dosage of the pulmonary surfactant to beadministered is equal to or higher than 80 mg per kg body weight,preferably from 100 to 200 mg per kg body weight. The preferred dose is100 mg per kg body weight.

The dosage of the surfactant to be administered varies with the size andmaturity of the infant, as well as with the severity of the infant'scondition. The skilled in the art will be readily able to determinethese factors and to adjust the dosage administered via the thin tube.

After administration of the surfactant, the thin tube is removed.However, the infant, depending on the severity of the individualcondition and depending on the response of the infant to the firstsurfactant treatment, may receive a second dose of pulmonary surfactant.In particular, if the needed FiO₂ is higher than 40% the surfactant canbe instilled by the thin tube, otherwise if the needed FiO₂ exceeds 60%,the surfactant can be instilled by endotracheal intubation undermechanical ventilation.

Said second dose may be equal to, higher or lesser than the first dose,depending on the needs and response of the infant.

The present invention is also directed to a kit comprising: comprising:a) a sterile pharmaceutical composition comprising a pulmonarysurfactant having a viscosity lower than 20 centipoise suspended in apharmaceutically acceptable aqueous medium at a concentration of atleast 40 mg/ml; b) a thin tube having a diameter comprised between 5 and12 Fr; c) a device for administering the surfactant at a controlledrate; and d) container means for containing the dosage form, the thintube and the device.

Advantageously the sterile pharmaceutical composition is supplied assingle-use glass vial.

Otherwise, in a particular embodiment, the sterile pharmaceuticalcomposition can be supplied directly in the device used foradministering the surfactant at a controlled rate.

The following examples illustrate the present invention.

EXAMPLES Example 1 Viscosity Measurement of a Suspensions of DifferentBatches Of Curosurf®

Rheological measurements were carried out at 25° C. with a rheometer SR200 (Rheometric Scientific) and 40 parallel plate geometry usingdifferent batches of Curosure, i.e of poractant alfa suspended inphysiological saline aqueous solution at a concentration of 80 mg/ml.

The instrument was calibrated to a gap of 0.7 mm.

The shear rate was varied between 0 and 500 s⁻¹.

For all batches Curosurf®, the viscosity (η) approaches awell-reproducible asymptotic value (max Shear Rate 500 s⁻¹) comprisedbetween 6 and 10 mPas (1 mPas 1 centipoise).

Example 2 Administration of 100 Mg/Kg Dose Poractant Alfa by GastricTube in Very-Low-Birth-Weight Infants Protocol of the Study

In a preliminary observational study no difference between infants aftersurfactant application without intubation and infants with standardtreatment was observed, despite the fact that infants treated withsurfactant application without intubation were significantly smaller.

The primary objective of the following study is to demonstrate that thetreatment of very-low-birth-weight (VLBW) infants with intratrachealinstillation of a pulmonary surfactant is able to reduce the frequencyof mechanical ventilation.

Secondary objectives of the study are to demonstrate that the proposedmethod:

-   -   is associated with a reduced duration and intensity of        mechanical ventilation; and    -   is associated with a reduced incidence of bronchopulmonary        dysplasia (BDP),    -   while being at least equivalent to standard treatment with        regard to the secondary outcome measures death, intraventricular        hemorrage grade III and IV (IVH), and periventricular        leukomalacia (PVL).

Design:

Prospective, randomized multi-center trial.

Study Population:

Inclusion criteria:

-   -   gestational age 26±0−28±6 weeks,    -   birth weight below 1500 grams,    -   Age 0-12 hours,    -   Informed consent.

Exclusion criteria:

Mechanical ventilation,

-   -   Participation in other studies.

Intervention:

Control-group:

-   -   CPAP if FiO₂ exceeds 0.25,    -   all other therapies according to local standards.

Intervention group:

-   -   CPAP if FiO₂ exceeds 0.25,    -   intratracheal surfactant via a gastric feeding tube if FiO₂        exceeds 0.3 (to keep oxygen saturation above 85%) and        Silverman-score>4    -   all other therapies according to local standards.

Intervention:

-   -   Surfactant is given at a dose of 100 mg surfactant per kg body        weight via a thin (gastric) tube into the trachea of the        spontaneously breathing infant.    -   CPAP is applied continuously during the procedure (nasal IPPV        may be applied).    -   Optional use of atropin (5 μg/kg body weight i.v.) prior to the        procedure.    -   As many doctors will not use sedation for intubation in the        delivery suite or in the first hours/minutes of life,        sedation/analgesia is not mandatory and at the discretion of the        individual neonatologist.    -   The gastric tube is placed with a Magill-forceps under direct        visualization of the vocal cords by means of a laryngoscope.    -   After placement of the gastric tube, the laryngoscope is removed        and surfactant (100 mg/kg body weight) is instilled into the        trachea during 1-5 minutes.    -   Thereafter, the gastric tube is removed.    -   Close observation of the child during the procedure is        mandatory.    -   Surfactant administration can be repeated if FiO₂ exceeds 0.4.    -   Intubation and intratracheal surfactant administration should be        considered if FiO₂ exceeds 0.6 or the child suffers from severe        respiratory distress.    -   All other treatments according to local standards.

Primary Outcome Measure:

-   -   Intubation and mechanical ventilation between the 25′ and        72^(th) hour of life or    -   FiO₂>0.6 (to keep oxygen saturation above 85%) between the        25^(th) and 72^(th) hour of life    -   pCO₂>65 mm Hg for more than two hours between the 25^(th) and        72^(th) hour of life.

Sample Size:

Based on current multi-center study data, we expect a frequency of theprimary outcome measure in the control group of 60% vs. 40% in theintervention group. Since 50% of the infants are randomized to thecontrol group, a total of 210 infants (105 in each group) will benecessary to test the primary hypothesis (p=0,05; beta-error 0,2;2-sided). Since the participating centers are treating 250 patients/yearwho are eligible for the study and we calculated a 60% inclusion rate, aperiod of 30 months would be sufficient to test the primary hypothesis.

Secondary Outcomes:

Ventilation rate, IVH, PVL, BPD, death, operation due to retinopathy(ROP), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC),intestinal perforation, hydrocephalus and ventricular-peritoneal-shunt,number of surfactant doses, total surfactant (mg/kg bodyweight), days onassisted ventilation, days on supplemental oxygen, duration ofhospitalization, weight gain per day, pneumothorax, other complicationsof prematurity (same definitions as for the genetic study).

Methods Against Bias:

Infants are randomized prior to intubation. To avoid the possible biasthat infants in the intervention group are not intubated although theymeet local intubation criteria, we defined a combined primary endpointusing a FiO₂>0.6 to gain a saturation >85% and/or pCO₂>65 mm Hg for morethan two hours during the 25-72^(th) hour of life as an indicator fortreatment failure. FiO₂-levels and pCO₂ levels are observed anddocumented by nurses. Blinding and a sham procedure in the control groupare not possible.

1. A method for treating a respiratory distress syndrome in a spontaneously breathing pre-term infant in need of such treatment, said method comprising the steps of: a) applying nasal Continuous Positive Airway Pressure (nCPAP) with a nasal device to said infant at a pressure of from 1 to 12 cm water; b) introducing a tube selected from the group consisting of gastric tube, nasogastric tube, arterial or suction catheter and having a outer diameter comprised between 5 and 12 Fr into the trachea of said infant; c) administering a pulmonary surfactant suspended in a pharmaceutically acceptable aqueous medium through said tube and d) removing said tube wherein the surfactant suspension is applied at a concentration of at least 40 mg/ml and has a viscosity lower than 20 mPas.
 2. The method of claim 1, wherein the viscosity is comprised between 5 and 15 mPas.
 3. The method of claim 2, wherein the viscosity is comprised between 6 and 10 mPas.
 4. The method of claim 1, wherein the concentration of the surfactant suspension is comprised between 40 and 80 mg/ml.
 5. The method of claim 1, wherein the surfactant is a modified natural surfactant or a reconstituted surfactant.
 6. The method of claim 1, wherein nCPAP is applied with a nasal mask.
 7. The method of claim 1, wherein the pressure is from 2 to 8 cm water.
 8. The method of claim 1, wherein the surfactant is suspended in a buffered physiological saline aqueous solution.
 9. The method of claim 8, wherein the surfactant is suspended in a volume of not more than 3 ml.
 10. The method of claim 9, wherein the volume is not more than 2.5 ml.
 11. The method of claim 1, wherein the respiratory distress is the infant Respiratory Distress Syndrome (RDS).
 12. The method of claim 1, wherein the respiratory distress syndrome is due to meconium aspiration or pulmonary infection.
 13. A kit comprising: a) a sterile pharmaceutical composition comprising a pulmonary surfactant having a viscosity lower than 20 mPas suspended in a pharmaceutically acceptable aqueous medium at a concentration of at least 40 mg/ml; b) a tube having a diameter comprised between 5 and 12 Fr; c) a device for administering the surfactant at a controlled rate; d) container means for containing the dosage form, the gastric tube and the device.
 14. The kit of claim 13, wherein the sterile pharmaceutical composition is supplied as single-use glass vial.
 15. The kit of claim 13, wherein the sterile pharmaceutical composition is supplied directly in the device used for administering the surfactant at a controlled rate. 